Dr. Song is a rheumatologist with training in immunology and molecular biology. There is significant evidence suggesting underlying dysregulation not only of inflammatory responses but also of the coagulation system in rheumatoid arthritis (RA). Dr. Song's research interests lie in investigating how joint inflammation in RA interplays with dysregulation of the coagulation system. To date, little is known about the molecular links between inflammation and coagulation in RA and other inflammatory diseases. Dr. Song has generated preliminary data that demonstrates a marked increase in arthritis in an animal model with deficiency of carboxypeptidase B (CPB), a plasma enzyme that contributes to the stability of blood clots. This data led him to propose the hypothesis that CPB is involved in the interaction of inflammation and coagulation in RA. Interestingly, it has been found that CPB interacts with several proinflammatory substrates and removes carboxy-terminal arginines. In this KOS, he proposes to determine how CPB down-regulates inflammation in arthritis by acting on proinflammatory substrates including osteopontin, complements components and bradykinin. This application also details a carefully thought out career development plan that includes rich interaction with other laboratories at Stanford, attendance at seminars and scientific meetings, supervision of students and technicians, and classes in immunology and bioinformatics. Dr. Song has strong institutional support that will allow him to focus on these studies with minimal distraction to non-research activities. This KGB mentored Clinical Scientist Career Development Award will facilitate Dr. Song's transition from a rheumatologist to a physician scientist who is fully competent to investigate the link between inflammation and coagulation in his own academic laboratory through independent, investigator-initiated funding. RELEVANCE (See instructions): This research is directly related to public health as 1% of the US population suffers from RA, and RA is a significant cause bf morbidity and mortality. Out data demonstrate that CPB is a natural modulator of inflammation, in addition to its recognized role as a fibrinolysis inhibitor. The proposed experiments will provide insights into the pathogenesis of RA which could lead to new therapeutic approaches.